Lydia Scarfò, MD, Assistant Professor of Internal Medicine, Università Vita-Salute San Raffaele, Milan, Italy, discusses the phase 2, multi-center IMPROVE study on the use of a minimal residual disease (MRD)-driven strategy with ibrutinib and venetoclax to improve the depth of response (DOR) in relapsed and refractory (R/R) chronic lymphocytic leukemia (CLL). These data were presented at the 2021 EHA Virtual Congress.

Transcript

Hi, my name is Lydia Scarfo. I'm Assistant Professor of Internal Medicine at Universit‡ Vita-Salute San Rafaelle in Milan and consultant hematologist at the strategic research program at Hospitale San Rafaelle here in Milan.

When we designed the study, there were few data on the combination of ibrutinib and venetoclax in vitro. They confirmed the synergistic profile of the 2 drugs, meaning that ibrutinib is a BTK inhibitor, so it is acting on the lymphoproliferative compartment, while venetoclax is a BCL2 inhibitor, so it's promoting apoptosis.

The combination of these 2 agents is targeting 2 key mechanism of survival and proliferation of leukemic cells. There were only few data on the combination of ibrutinib and venetoclax in mantle cell lymphoma (MCL).

There is available evidences on the efficacy of venetoclax used as single agent to obtain undetectable MRD in bone marrow and peripheral blood of patients with CLL at the time of relapse. Data were also available on the efficacy of ibrutinib in improving the depth of the response in combination and after chemoimmunotherapy regimens, so we designed the so-called IMPROVE study.

In this phase II study, we had all the patients with relapse refractory (R/R) CLL. We followed MRD-driven strategy to improve the DOR. Basically, all patients enrolled into the trial received 12 months of venetoclax monotherapy, and then, based on the results of MRD, the treatment was differentiated.

Those with undetectable MRD in both peripheral blood and bone marrow stopped treatment and continued follow-up only, while those who had still-detectable MRD added ibrutinib to venetoclax.

Then we regularly checked the MRD status. Those who obtained undetectable MRD in both peripheral blood and bone marrow stopped both treatments. At the end of 24 months of venetoclax therapy and 12 months of combination of venetoclax and ibrutinib, those who still have detectable residual disease continue with ibrutinib single-agent. We enrolled 38 patients.

We were quite impressed by the fact that, in 45% of patients, venetoclax monotherapy was able to obtain undetectable MRD. So, 45% of patients stopped patient, having received basically venetoclax monotherapy, while the other 55% of patients—19 patients—continued venetoclax for a total of 24 months, and added ibrutinib.

In 84% of cases, those with detectable MRD became undetectable, so they could stop treatment. After a median follow-up of about 33 months, the 24-month progression-free survival (PFS) was still 91%.

I'd say they're impressive results. The advantage of the design of our study, because after this study, other studies investigated the combination of ibrutinib and venetoclax, is that we are tailoring treatment based on their response. Meaning that there is a relevant proportion of patients who are able to obtain undetectable MRD with venetoclax monotherapy, so there is no need to intensify treatment.

While we could reach undetectable MRD in a relevant proportion of patients with the combination of both agents that are stopping both therapies. We identified very few—3—in the total core patients who needed to continue treatment, because they were still carrying detectable MRD. I just say this approach was able to tailor treatment based on disease response in our cohort.

We are learning that fixed-duration therapies are possible, even with these novel targeted agents that in most cases were initially used as continuous treatment, so probably obtaining deep responses can allow us to stop treatment and avoid the occurrence of, for example, resistance mutations.

We need to gather more information on these before using this combination in clinical practice. I say the initial results of our study are supporting the use of an MRD-driven strategy to tailor treatment. This might be in the future the way to go to avoid the one-size-fits-all approach and define the best treatment option for each patient.

Our next steps are basically to prolong follow-up and to understand the interval before disease progression and need for a next-line treatment in our cohort, and especially in patients who stopped treatment because of undetectable MRD.

We have amended the study to allow retreatment with venetoclax for patients who progressed and require treatment after stopping the initial therapy in undetectable MRD status. In the near future, we hope to use a similar approach in first-line settings, so to avoid chemoimmunotherapy administration in first line, and start from the beginning with targeted agent combinations.

I just want to point out that the tolerability profile was also very favorable. With venetoclax in the initial studies, we faced the issue of tumor lysis syndrome, but in our study, no patients experienced laboratory or clinical tumor lysis syndrome.

The combination of the 2 drugs when used was quite safe, and very few grade 3 or 4 adverse events were reported. In terms also of safety, there are no signals.

Scarfò L, Heltai S, Albi E, et al. MRD-driven treatment intensification with sequential addition of ibrutinib to venetoclax in R/R CLL: The IMPROVE study. Presented at: the 2021 EHA Virtual Congress; June 9-17, 2021; virtual. Abstract EP634.